Cardiovascular disease is the leading cause of morbidity and mortality in the US, afflicting over 58 million Americans. Angiogenic factors can increase vascularization and improve perfusion in ischemia. Scatter factor/hepatocyte growth factor (SF/HGF) may be superior to other angiogenic factors because of multiple actions on components of the angiogenic cascade and anti-apoptotic properties. Our Phase I studies demonstrated therapeutic angiogenesis by SF/HGF gene therapy in rat and mouse models of peripheral ischemia. We will confirm and extend this work by obtaining detailed dose and time course information with long-term follow-up for therapeutic benefit as well as adverse effects in the mouse hindlimb ischemia model. We will also examine the benefits of SF/HGF gene therapy in treating peripheral ischemia in aging mice and in mice with diabetes. The rabbit model of peripheral ischemia will be used to assess the effectiveness of SF/HGF gene therapy by physiological assessment of blood flow and hindlimb perfusion pressure and anatomical assessment of collateral vessel development, capillary density and muscle atrophy. In additional studies we will compare the effectiveness of SF/HGF gene therapy with VEGF therapy. The goal of these studies is to bring SF/HGF gene therapy to clinical practice. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE